Activation of the YAP/KLF5 transcriptional cascade in renal tubular cells aggravates kidney injury
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AbstractThe Hippo/YAP pathway plays a critical role in tissue homeostasis. Our previous work demonstrated that renal tubular YAP activation induced by double knockout (dKO) of the upstream Hippo kinases Mst1 and Mst2 promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Here, we show that tubular YAP was already activated 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell overproliferation, tubular injury, and renal inflammation induced by UUO or cisplatin. YAP promoted the transcription of the transcription factor KLF5. Consistent with this, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell overproliferation, tubular injury, and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, where tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell overproliferation, tubular injury, and renal inflammation.
Acceptance Date24/02/2024
All Author(s) ListYang Liu,Yu Wang, Chunhua Xu, Yu Zhang, Yang Wang, Jinzhong Qin, Hui-Yao Lan, Li Wang, Yu Huang, Kingston Kinglun Mak, Zhihua Zheng, Yin Xia
Journal nameMolecular Therapy
Year2024
Month5
Volume Number32
Issue Number5
PublisherElsevier
Pages1526 - 1539
ISSN1525-0016
eISSN1525-0024
LanguagesEnglish-United Kingdom
KeywordsHippo, KLF5, MST1, MST2, UUO, YAP, kidney, tubular injury

Last updated on 2024-16-10 at 14:12